Most patients with squamous cell cell carcinomas of the head and neck (SCCHN) present with disease that is incurable or likely to fail conventional therapy. Furthermore, unacceptable functional and cosmetic deficits are produced in many patients that are cured with conventional therapy. Effective cytotoxic therapy has the potential to cure patients with advanced disease (induction trials), reduce the undesirable consequences of conventional therapy (organ preservation trials) and prevent recurrences following conventional therapy (adjuvant trials). Cytotoxic therapy has shown such potential only when microscopic disease is eradicated. Clinical trials are hampered by wide variations in patterns of cytotoxic responses following induction therapy or recurrences following conventional therapy in patients with similar clinical characteristics and amounts of disease. Attempts to predict the clinical outcome of individual patients on the basis of differences in clinical or morphological parameters have not been successful. The flow cytometric measurements of cellular DNA content in recurrent and previously untreated patients, as well as serial measurements in advanced patients undergoing cytotoxic therapy, indicate that patients with DNA diploid tumors or significant subpopulations do not achieve microscopic eradication of tumor. In advanced patients undergoing surgery as initial therapy, reduced recurrence rates and superior disease free survival and absolute survival are associated with DNA diploid tumors. Significant differences in the patterns of tumor growth and stromal interface for DNA diploid and aneuploid tumors may account for the differences in local-regional relapse rates following surgery. DNA content parameters have been serially determined in patients with SCCHN entered onto Southwest Oncology Group induction trials (SWOG-8855), are currently being determined in the Nasopharyngeal Intergroup Trial (INT-0099), and have been determined in a portion of the patients entered onto the Intergroup Resectable Trial (INT-O034). Commitments have been made by the Southwest Oncology Group, the Radiation Therapy Oncology Group (RTOG) and the Eastern Cooperative Oncology Group (ECOG) to retrospectively analyze the remaining patient specimens from INT-0034 and prospectively determine the cellular DNA content parameters in the current Intergroup trials for Advanced Unresectable Disease (INT-0126) and Laryngeal Preservation. The determination of DNA ploidy classes may aid in the prediction of clinical outcome and selection of patients with advanced SCCHN in clinical trials.